Draft guidance on human and veterinary drug submissions based on promising evidence and terms and conditions: Overview

On this page

• Purpose
• Introduction
• Scope and application
• Policy objectives and statements
• Potential sources of promising evidence of efficacy
• Definitions
• Note about guidance documents in general

Purpose

This guidance document outlines the:

• requirements for human and veterinary drug submissions that are based on promising evidence of clinical efficacy
• terms and conditions (T&Cs) when issuing a notice of compliance (NOC) for drugs authorized based on promising evidence of clinical efficacy

Introduction

The Food and Drugs Act (FDA) and its regulations give Health Canada the authority to regulate food, drugs, medical devices and cosmetics. All drugs intended to be marketed for human and veterinary use in Canada are reviewed to ensure that they meet the requirements of the FDA and its regulations. As the federal regulator for drugs, Health Canada's role is to thoroughly evaluate the information supporting a drug submission. Through scientific assessments, the review process is to ensure a drug:

• is safe for human and veterinary use, with acceptable risks compared to benefits
• is effective for the intended treatment or condition
• meets quality standards in manufacturing, purity, and consistency

To be authorized for sale, drugs for human and veterinary use must meet all applicable requirements in Part C, Division 1 of the Food and Drug Regulations (regulations). Drugs that meet the definition of a new drug under Part C, Division 8 of the regulations must also satisfy the requirements of Division 8. If there is insufficient evidence to support the safety, effectiveness or quality of a new drug, Health Canada will not grant market authorization for the drug.

New drugs under development for serious or severely debilitating conditions may have promising evidence of clinical efficacy, but the available data is limited. Health Canada recognizes that efficacy data may be limited due to various important considerations such as:

• availability of only preliminary or interim data on relevant endpoints
• long duration of time required to collect data on conventional endpoints or
• small number of patients who participated in clinical trial(s) due to limited availability of patients, such as in cases of rare diseases or conditions

However, while the available data may be limited, it may provide promising evidence that the drug could help reduce or prevent serious signs, symptoms, or adverse clinical outcomes of a disease or condition. The evidence may demonstrate that the drug has a clinical benefit and that the benefits outweigh the known risks relating to the drug's use. New drugs that are supported by information that has demonstrated promising evidence of clinical efficacy should be made available to individuals who have serious or severely debilitating conditions where there is an unmet medical need. If the information supporting the drug demonstrates the benefits outweigh the known risks and if it satisfies the requirements of the FDA and the regulations, a NOC may be issued to allow market authorization of the drug. However, in the case of a drug supported by promising evidence of efficacy, significant uncertainties remain with the effectiveness of the drug. As such, the available evidence may satisfy the requirements of the FDA and the regulations if additional confirmatory studies are performed to verify the new drug's effectiveness for further assessment.

When we authorize a drug to be marketed in Canada, we assign a drug identification number (DIN) to the manufacturer, which is printed on the package labels. A DIN indicates that the drug met the relevant requirements of the FDA and its regulations and the evidence demonstrated the drug has a favourable benefit-risk profile. To be considered for market authorization of new drugs that are supported by promising evidence of clinical efficacy, we will consider imposing terms and conditions (T&Cs) to address the significant uncertainties regarding the effectiveness of the drug. T&Cs may be imposed on the DIN of the drug when determining to issue the NOC. These T&Cs will require market authorization holders (MAHs) to conduct further studies to confirm the effectiveness of the new drug and further confirm that it maintains a favourable benefit-risk profile as was determined at the time of authorization.

Scope and application

This draft guidance document applies to new drug submissions (NDS) and supplements to new drug submissions (SNDS) for human or veterinary drugs that meet the following criteria:

• the submission is for a human or veterinary drug that meets the definition of a new drug under C.08.001 and
• the information supporting the new drug is based on promising evidence of efficacy

It explains the:

• process for filing a NDS or SNDS based on promising evidence of efficacy
• review of these drug submissions
• process for human drug manufacturers to apply for shortened screening and review targets
• application of the T&Cs and when the Minister may take these into account during the review of a submission based on promising evidence of efficacy

The focus of this guidance is on drug submissions based on promising evidence of clinical efficacy where T&Cs are considered by applying section C.08.003.2 of the FDR. For general information on T&Cs and its application, refer to:

• Draft guidance on terms and conditions for human and veterinary drugs

Policy objectives and statements

A NDS or SNDS must be supported by sufficient information as required by the regulations for a new drug to be considered for market authorization.

Drug submissions supported by clinical data demonstrating promising efficacy, supported by subsequent confirmatory evidence, may be sufficient to support regulatory decision-making. However, until confirmatory evidence is fully assessed, significant uncertainties about the drug's effectiveness remain. In such cases, early market access may be considered appropriate for drugs intended to treat serious or severely debilitating diseases.

To be considered for market authorization, T&Cs will be considered to address the significant uncertainties with the clinical effectiveness of the drug. Such considerations may be applied when the proposed use of the new drug is for serious or severely debilitating disease or condition and its recommended purpose and conditions of use do not fall within those of any other drug that has been assigned a DIN. Alternatively, it may apply if the new drug is significantly more effective or presents a significantly lower risk than an existing drug with an active DIN.

Our objective in considering drug submissions supported by promising evidence of clinical efficacy is to enable earlier access to promising new therapies while ensuring that the drug's overall benefit-risk profile remains favourable.

Potential sources of promising evidence of efficacy

We may accept data from clinical trials or veterinary studies that use surrogate markers. To be validated, a surrogate marker must undergo extensive testing to confirm that its effect accurately predicts clinical benefits. Data from non-validated surrogate markers cannot replace evidence showing a drug's impact on recognized clinical endpoints.

In any case, while the evidence for efficacy is promising, these new drugs must demonstrate that they meet safety and quality requirements as well as other requirements for a NDS or a SNDS.

For human drugs, relevant evidence may be derived from:

• acceptable surrogate markers from clinical studies that require confirmation in additional clinical studies
• Phase II clinical studies that require confirmation in one or more Phase III studies
  • this may include cases in which Phase II results are available for only a specific disease stage or patient subgroup
• one or more small or moderately sized Phase III clinical studies that require confirmation in at least one additional larger, adequately sized, Phase III and/or Phase IV study
  • this may include cases in which limited Phase III results are available for only a specific disease stage or patient subgroup and additional data are required to support use of the drug in other disease stages and/or a broader patient population

For veterinary drugs, relevant evidence may be derived from:

• pilot studies where more animal subjects are needed or
• interim analysis of pivotal efficacy study

Results obtained from studies are evaluated in the context of additional information, such as:

• advisory panels
• expert opinions
• literature reviews
• real world evidence and/or
• pharmacokinetic/pharmacodynamic studies

Definitions

Advance consideration of promising evidence (ACPE) status:

A status granted to human new drug submissions (NDS) and supplements to new drug submissions (SNDS) resulting in reduced screening and review targets when certain criteria have been met.

Available therapies:

Drugs for which a DIN has been assigned and has not been cancelled for a specified recommended purpose and conditions of use. Products available through the special access program (SAP), emergency drug release (EDR), or the urgent public health need (UPHN) list are not considered "available therapies" for drug submissions based on promising evidence of clinical efficacy.

Clinical benefit:

Outcomes that have a positive impact on the course of a disease.

Market authorization holder (MAH):

The market authorization holder (MAH) is also referred to as sponsor or manufacturer. The MAH is the legal entity that holds the NOC and the DIN.

Promising clinical evidence:

Evidence based on well-designed and well-conducted clinical trials and veterinary studies establishing that the drug product has an effect on an acceptable surrogate or intermediate clinical endpoint that is reasonably likely to predict clinical benefit.

Request for advance consideration of promising evidence (ACPE):

A form for drug submissions with promising evidence of clinical efficacy that, once completed, is used to determine if a submission will meet the criteria for reduced screening and review targets.

SNDS-Confirmatory (SNDS-C):

A supplement to a new drug submission (SNDS) - confirmatory is a submission of the results from the confirmatory clinical trials and/or veterinary studies specified in the 'Terms and conditions letter'.

Surrogate markers:

Parameters based on available evidence which predict an effect of a drug on recognized clinical outcomes such as morbidity and mortality. A validated surrogate marker is predictive of the clinical benefit of a drug.

Note about guidance documents in general

Guidance documents provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. They also provide guidance to Health Canada staff on how mandates and objectives should be met fairly, consistently and effectively.

Guidance documents are administrative, not legal, instruments. This means that flexibility can be applied. However, to be acceptable, alternate approaches to the principles and practices described in this document must be supported by adequate justification. They should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As always, Health Canada reserves the right to request information or material, or define conditions not specifically described in this document, to help us adequately assess the safety, efficacy or quality of a therapeutic product. We are committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read along with the relevant sections of the regulations and other applicable guidance documents.